The delivery of drugs in pressurized metered-dose inhalers (MDI) currently employs the chlorofluorocarbons as propellants. As a result of the phase out of chlorofluorocarbons (potential depletion of the ozone layer), products marketed using chlorofluorocarbons must be reformulated using hydrofluoroalkane (HFA) propellants e.g 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), marketed by Du Pont Chemicals, Wilmington, Del., USA. The solvent behavior of the proposed alternative propellants is quite different from that of the chlorofluorocarbons. Difference in the physicochemical properties, such as polarity, vapor pressure and density, has posed challenges to the development of drug products in pressurized metered-dose inhalers for pulmonary delivery using hydrofluoroalkanes as propellants [Byron et al., Resp. Drug Deliv., 4 (1994)].
Numerous patent documents address these differences in physiochemical properties in formulations for inhalation. U.S. Pat. No. 5,492,688 relates to MDI formulations which utilize greater than 90% by weight of HFA 134a as the sole propellant, less than 5% w/w of micronized drug particles and less than 5% w/w of a polar surfactant selected from the group consisting of polyethylene glycol 300, diethylene glycol monoethyl ether, polyoxyethylene 20 sorbitan monooleate, propoxylated polyethylene glycol, and polyoxyethylene 4 lauryl ether.
World patent WO 91/04011 describes a self-propelling powder aerosol composition containing finely-divided, pre-micronized solid drug coated with a single non-perfluorinated surface-active dispersing agent suspended in an aerosol propellant in which the dispersing agent is substantially insoluble. Suitable dispersing agents include various oils, sorbitan oleates, polyoxyethylene sorbitans, lecithins and polyoxyethylene among others. T he quantity of surfactant used is kept to a minimum to avoid particle agglomeration and increase particle size.
World patent application 96/19197 relates to a pharmaceutical aerosol formulation comprising (a) a hydrofluoroalkane propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C8-C16 fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide, which surfactant enhances the systemic absorption of the polypeptide in the lower respiratory tract. World patent application 96/19198 by the same inventors relates to a pharmaceutical aerosol formulation comprising a HFA propellant; a physiologically effective amount of a medicament for inhalation; and a surfactant which is a C8-C16 fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide. Both patents describe physical mixtures of active and surfactant in the propellant, with no prior encapsulation steps involved.
World patent application 96/40089 relates to a pharmaceutical aerosol formulation a pharmaceutical composition for aerosol delivery containing a medicament, a halogenated alkane propellant, and a biocompatible C16+-unsaturated vegetable oil.
World patent application 90/11754 relates to an aerosol formulation containing, as active ingredient, an azole antifungal in a form suitable for administration by inhalation.
World patent application 94/21228 relates to a medicinal aerosol formulation having a diol/diacid condensate as a dispersing agent, a propellant, and a therapeutically effective amount of a particulate drug.
World patent application 96/06598 relates to a pharmaceutical composition for aerosol delivery comprising a medicament, a non-chlorofluorocarbon propellant, and a polyglycolyzed glyceride.
World patent application 92/06675 relates to an aerosol formulation containing a therapeutically effective amount of beclomethasone 17,21 diproprionate, hydrofluorocarbon 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) propellant or a mixture and ethanol in an amount effective to solubilize the beclomethasone 17,21 diproprionate in the propellant. Substantially all the beclomethasone 17,21 diproprionate is dissolved in the formulation, and it is substantially free of any surfactant.
World patent application 93/05765 relates to a pressurized aerosol composition comprising a liquefied hydrofluoroalkane, a powdered medicament dispersible therein and a polymer soluble in the liquefied hydrofluoroalkane. The polymer includes, amide containing units or carboxylic acid ester containing units as recurring structural units.
U.S. Pat. No. 4,174,295 relates to a propellant composition for use with aerosols, the composition consisting essentially of a mixture of from 5 to 60% by weight, based on the total weight of the propellant composition, of a hydrogen-containing fluorocarbon selected from CH.sub.2 F.sub.2 and CF.sub.3 --CH.sub.3, and from 40 to 95% by weight, based on the total weight of the propellant composition, of a hydrogen-containing chlorofluorocarbon or a hydrogen-containing fluorocarbon, each selected from CF.sub.3 --CHClF, CF.sub.3 --CH.sub.2 Cl, CF.sub.3 --CH.sub.2 F, CClF.sub.2 --CF.sub.3 or CHF.sub.2 --CH.sub.3.
U.S. Pat. No. 5,118,494 relates to a suspension aerosol formulation, including: a propellant comprising a hydrofluorocarbon selected from 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227), or a mixture, a therapeutically effective amount of a powdered medicament; and between about 0.001 and 0.6% by weight based on the total weight of the formulation of a perfluorinated carboxylic acid or ester as surface-active dispersing agent. The formulation exhibits substantially no crystallization of medicament over a prolonged period, is readily redispersible, and upon redispersion non flocculating so quickly as to prevent reproducible dosing of the medicament.
U.S. Pat. No. 5,126,123 relates to an aerosol inhalation drug formulation consisting essentially of a physiologically effective amount of a micronized inhalation drug and a 1,1,1,2-tetrafluoroethane-soluble, perfluoronated surfactant in suspension in 1,1,1,2-tetrafluoroethane.
U.S. Pat. No. 5,182,097 relates to an aerosol formulation for use in delivering medication to a patient via an inhalation device, comprising a propellant consisting solely of 1,1,1,2-tetrafluoroethane. The propellant represents at least 90% by weight of the aerosol formulation; an inhalable medicament dispersed or dissolved in a propellant, an inhalable medicant having a partition size less than 100 microns in diameter. The inhalable medicant represents no more than 5% by weight of aerosol formulation. Oleic acid employed as a surfactant for aiding in dispersing the inhalable medicant in the propellant, with oleic acid no more than 0.2% w/v of aerosol formulation.
U.S. Pat. No. 5,202,110 relates to an aerosol formulation for use in a metered dose inhaler, comprising a pharmaceutically acceptable inhalable propellant; a clathrate or molecular association of beclomethasone diproprionate employed as inhalable medicant dispersed or dissolved in a propellant. The clathrate or molecular association of beclomethasone diproprionate is formed with 1,1-dichloro-2,2,2-trifluoroethane, or 1,1-dichloro-1-fluoroethane, or dimethyl ether; the clathrate or molecular association having a particle size permitting inhalation.
U.S. Pat. No. 5,474,759 relates to an aerosol formulation consisting essentially of an effective amount of medicament; 1,1,1,2,3,3,3-heptafluoropropane (HFA 227); optionally, an excipient selected from a propylene glycol diester of a medium chain fatty acid or a triglyceride ester of a medium chain fatty acid. A surfactant is optionally present together with other excipients.
World patent application 96/32150 relates to a metered dose having, part or all of its internal surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, for dispensing an inhalation drug formulation of salmeterol, or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients.
World patent application 96/32151 relates to a metered dose inhaler having part or all of its internal surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, for dispensing an inhalation drug formulation of fluticasone propionate, or a physiologically acceptable solvate thereof, and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients.
World patent application 96/18384 relates to a pharmaceutical aerosol formulation of 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) or mixtures thereof as propellant; 1,1,2,2,3-pentafluoropropane as co-propellant; and particulate medicament.
World patent application 94/03153 relates to a pharmaceutical aerosol formulation of particulate beclomethasone diproprionate or an acceptable solvate together with a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which formulation is substantially free of surfactant.
World patent application 96/32099 relates to a metered dose inhaler having part or all of its internal surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, for dispensing an inhalation drug formulation of albuterol, or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients.
World patent application 93/11745 relates to a pharmaceutical aerosol formulation of a particulate medicament, a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant and up to 5% w/w based upon propellant of a polar cosolvent, which formulation is substantially free of surfactant.
World patent application 93/11743 relates to a pharmaceutical aerosol formulation comprising particulate medicament of salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or their physiologically acceptable salts and solvates, and a fluorocarbon or hydrogen-containing chlorofluorocarbon. The formulation is substantially free of surfactant.
World patent application 93/15741 relates to a pharmaceutical aerosol formulation of beclomethasone dipropionate monohydrate, the particle size of substantially all the monohydrate being less than 20 microns; at least 0.015% w/w of the formulation of water in addition to the water of crystallization associated with the monohydrate; and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.
World patent application 93/11744 relates to pharmaceutical aerosol formulation of a particulate medicament and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, the formulation is substantially free of surfactant and when the medicament is other than salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or physiologically acceptable salts or solvate thereof.